title: Reversible neural stem cell niche dysfunction in a model of multiple sclerosis.
abstract: OBJECTIVE
  The subventricular zone (SVZ) of the brain constitutes a niche for neural stem and progenitor cells that can initiate repair after central nervous system (CNS) injury. In a relapsing-remitting model of experimental autoimmune encephalomyelitis (EAE), the neural stem cells (NSCs) become activated and initiate regeneration during acute disease, but lose this ability during the chronic phases of disease. We hypothesized that chronic microglia activation contributes to the failure of the NSC repair potential in the SVZ.
  
  
  METHODS
  Using bromodeoxyuridine injections at different time points during EAE, we quantified the number of proliferating and differentiating progenitors, and evaluated the structure of the SVZ by electron microscopy. In vivo minocycline treatment during EAE was used to address the effect of microglia inactivation on SVZ dysfunction.
  
  
  RESULTS
  In vivo treatment with minocycline, an inhibitor of microglia activation, increases stem cell proliferation in both naive and EAE animals. Minocycline treatment decreases cortical and periventricular pathology in the chronic phase of EAE, improving the proliferation of Sox2 stem cells and NG2 oligodendrocyte precursors cells originating in the SVZ and their differentiation into mature oligodendrocytes.
  
  
  CONCLUSIONS
  These data suggest that failure of repair observed during chronic EAE correlates with microglia activation and that treatments targeting chronic microglial activation have the potential for enhancing repair in the CNS.
authors.affiliation: Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stine
authors.initials: S
authors.lastname: Rasmussen
authors.forename: Jaime
authors.initials: J
authors.lastname: Imitola
authors.forename: Angel
authors.initials: A
authors.lastname: Ayuso-Sacido
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Starossom
authors.forename: Pia
authors.initials: P
authors.lastname: Kivisäkk
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
authors.forename: Morten
authors.initials: M
authors.lastname: Meyer
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Garcia-Verdugo
authors.forename: Samia J
authors.initials: SJ
authors.lastname: Khoury
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D008911:Minocycline / Q000494:pharmacology; D009103:Multiple Sclerosis; D018991:Myelin Proteolipid Protein / Q000009:adverse effects; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000009:adverse effects; D055502:Secondary Prevention; D055153:Stem Cell Niche / Q000187:drug effects / Q000473:pathology*; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151); D008911:Minocycline; D001973:Bromodeoxyuridine